1. Source of the Invention
This invention was made with support from Dow Chemical Company under Contract No. 443120-57276-3. Dow Chemical Company may have some rights in this invention.
2. Field of the Invention
The present invention concerns the asymmetric synthesis of beta-amino alcohols from chiral or achiral enamines. The synthesis utilizes chiral organoboranes having a high steric bulk under conventional hydroboration conditions.
3. Description of the Related Art
Enantiomerically pure beta-amino alcohols play an increasingly important role in the treatment of a wide variety of human disorders, see Ref. (1) below. These alcohols are also useful as chiral auxiliaries in organic synthesis, see Ref. (2).
A commercially safe, economical route to chiral amino alcohols has been the goal of a number of academic and industrial groups. Some art of general interest is as follows:
C. T. Goralski et al., U.S. Pat. No. 4,886,924.
C. T. Goralski et al., U.S. Pat. No. 4,895,996.
H. C. Brown et al. (1988) Accounts for Chemical Research, Vol. 21 (#8), p. 287.
More specific references are described below and are referred to in the subsequent text as (Ref. 1) or (1), etc.
Some art of interest is listed as follows:
1. M. Grayson, Ed. (1982), Kirk-Othmer Encyclopedia of Chemical Techology, Vol. 17, pp. 311-345. PA0 2. (a) K. Tomioka (1990) Synthesis, p. 541; (b) R. Noyori et al., (1991) Ang. Chem. Int. Ed. Engl., Vol. 1, p. 49. PA0 3. (a) S. Miyano et al. (1981) J. Org. Chem., Vol. 48, p. 3608; (b) W. H. Frishman (1981) New Eng. J. Med., Vol. 305, p. 500; (c) R. J. Lefkowitz, Ann. Rep. Med. Chem., Vol. 15, p. 217; (d) E.J. Corey, et al. (1991) J. Org. Chem., Vol. 56, p. 442. PA0 4. (a) D. Enders (1981) ChemTech, Vol. 8, p. 504; (b) G.M. Coppola et al. (1987) Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids, Wiley-Interscience: New York, p. 1-4. PA0 5. (a) M. Kitamura et al. (1989) J. Am. Chem. Soc., Vol. 111, p. 6071; (b) M. Kitmura (1989) J. Am. Chem. Soc., Vol. 111, p. 4028; (c) N. Oguni et al. (1988) J. Am. Chem. Soc., Vol. 110, p. 7877; (d) K. Soai et al. (1987) J. Am. Chem. Soc., Vol. 109, p. 7111; (e) E. Corey et al. (1986) J. Am. Chem. Soc., Vol. 108, p. 7114; (f) T. Imamoto et al. (1980) Chem. Lett. p. 45; (g) F. Leyendecker et al. (1983) Tetrahedron Lett., Vol. 24, p. 3513. PA0 6. J. March (1985) Advanced Organic Chemistry, 3rd Ed., Wiley-Interscience: New York, pp. 368, 738-740. PA0 7. (a) G.M. Coppola et al. (1987), Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids, Wiley Interscience, New York, N.Y., pp. 53, 85, 115, 133, 159, 188. PA0 8. (a) H. Brown et al. (1987) J. Org. Chem., Vol. 52, p. 4014; (b) C. Goralski (1987) Final Report, R. B. Wetherill Laboratories of Chemistry, Department of Chemistry, Purdue University; (c) B. Singaram et al. (1991) J. Org. Chem., Vol. 56, p. 5691. PA0 9. (a) H. Brown et al. (1989) J. Am. Chem. Soc., Vol. 111, p. 384; (b) B. Singaram et al. (1991) J. Org. Chem., Vol. 56, p. 1543.
(b) L. Overman et al. (1985) J. Org. Chem., Vol. 50, p. 4154. PA1 alkyl having from 1 to 20 carbons; PA1 aryl having from 6 to 20 carbons; PA1 or R.sup.1 and R.sup.2 together form a cyclic ring having from 4 to 10 carbons with the proviso that one of R.sup.1 or R.sup.2 contains a carbon atom; PA1 R.sup.3 and R.sup.4 are each independently selected from alkyl or aryl groups; PA1 R.sup.3 and R.sup.4 together form a ring structure including the nitrogen atom in the ring having from 4 to 10 carbons; or PA1 R.sup.3 and R.sup.4 together form a ring structure including the nitrogen atom in the ring structure having from 4 to 10 carbon atoms and also includes a second heteroatom independently selected from oxygen, nitrogen or sulfur; PA1 R.sup.5 is independently selected from hydrogen, alkyl or aryl as defined hereinabove from a chiral or achiral enamine, which process comprises: PA1 (a) contacting a chiral or achiral enamine of the structure ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are defined hereinabove with a chiral borane of the structure: ##STR5## wherein R.sup.6 is independently selected from an aliphatic group, aromatic group, arylalkyl group, or alicyclic group having 6 to 50 carbon atoms, each having at least one chiral atom, and PA1 R.sup.7 is independently selected from hydrogen or R.sup.6, PA1 in a dipolar aprotic solvent at a temperature of between about +50.degree. and -50.degree. C. at ambient pressure for a time effective to react with the C.dbd.C bond, PA1 (b) contacting the reaction product of step (a) with solid or aqueous base and 5% to 50% by weight of a mild oxidizing agent is added gradually under ambient conditions for a time effective to produce the chiral beta-aminoalcohol wherein the chiral amino alcohol has an enantiomeric excess (ee) of one isomer over the other of about 50% or greater.
All patents, patent applications, articles, standards etc. cited in this application are incorporated herein by reference in their entirety.
Some examples of .beta.-amino alcohols that serve as valuable therapeutic agents are the .beta.-blockers Bevantolol, (Ref. 3a), Denopamine (3d) and Propranolol (3b,c) shown below: ##STR1##
The importance of enantiomeric purity in pharmaceutical compounds has been demonstrated by the debilitating and sometimes tragic side-effects caused by the presence of the non-therapeutic enantiomer of an otherwise beneficial drug (Ref. 1,3b,4). Naproxen is one isomer of a chiral antiinflammatory drug used extensively for arthritis. Naproxen must be resolved into the (R) and (S) forms. The (S)-isomer is therapeutic. The (R)-isomer concentrates in the human liver and can be fatal. One optical isomer of thalidomide is therapeutic. The other isomer causes severe birth defects (4).
Enantiomerically pure .beta.-amino alcohols have also been shown to be exceedingly effective chiral auxiliaries in asymmetric carbon-carbon bond forming reactions such as additions of diethylzinc to aldehydes (5a,5d) (see FIG. 1), or conjugate additions of organocuprate reagents to .alpha.,.beta.-unsaturated carbonyl compounds (see FIG. 2).
A few methods are reported for synthesizing racemic .beta.-amino alcohols (Ref. 6). Additionally, enantiomerically pure .beta.-amino alcohols are presently available through reactions of amino acids (7a), kinetic resolution of racemic mixes of amino alcohols (3a), or chromatographic methods (7b). The reduction of amino acids to the corresponding amino alcohols is currently economically feasible only for the naturally occurring L-amino acids. Kinetic resolution or chromatography result in the immediate loss of at least 50% of possible product and often involves laborious separations. The only synthetic methodology available for the direct synthesis of amino alcohols in high yields might be the amination of chiral epoxides. However, this method suffers from the limitations that chiral epoxides are not readily available, are expensive, and only mono-substituted and trans symmetrical disubstituted epoxides can be used or a mixture of products results as shown below in Equations (1) and (2). ##STR2## where R' and R" are alkyl or aryl.
The high reactivity of the enamine double bond, the most reactive double bond known in the hydroboration reaction, potentially makes it possible for compounds to undergo hydroboration by chiral boranes, e.g. either mono- or diisopinocampheyl-borane, resulting in amino alcohols of high enantiomeric purity. A commercial need, therefore, exists for a safe, simple, straightforward economic process to produce chiral .beta.-amino alcohols in high enantiomeric purity (or enantiomeric excess-ee). The present invention achieves this goal by utilizing bulky chiral organoboranes.